Metabolism/Biotransformation

Question 1

[13-minute video]: p450 enzyme system

Answer 1

💊

Question 2

Define metabolism from a pharmacological perspective.

Answer 2

Metabolism is the biotransformation of absorbed or endogenous compounds into more polar molecules which are more readily excreted renally. [The metabolic products may be less active or more active than the original compound or inactive.]

Question 3

Briefly discuss the phases of metabolism.

Answer 3

Phase I: compounds converted to more polar metabolites by introducing or unmasking a functional group lie -OH, -NH2, -SH, -COOH.

Phase II: The altered molecule further reacts with endogenous substrates like glucuronic acid, sulfate, acetate, or an amino acid to form more highly polar conjugates.

Phase III: These are processes involving the transport of drug metabolites out of cells. This involves two major families of transport proteins: ABC (ATP-binding cassette) transporters and SLC (solute carrier) transporters.

Further notes:
Sometimes phase II may precede phase I e.g. isoniazid to N-acetly conjugate (phase II). The conjugate is then hydrolyzed to isonicotinic acid and acetlyhydrazine (phase I).

Question 4

Every tissue has some ability to metabolize drugs, but the major site is the ________.

Answer 4

liver

Further notes:
➤ Others with notable activity are the GIT, lungs, kidneys, and the skin.
➤ Certain drugs, such as clonazepam and chlorpromazine, are more extensively metabolized in the intestinal wall than in the liver. This means a significant portion of these drugs is broken down before they even reach the liver.

Question 5

Define first-pass effect.

Answer 5

The first pass effect is the process by which the concentration of an orally administered drug is greatly reduced before it reaches the systemic circulation, primarily due to metabolism in the liver and gut wall [to a lesser extent].

Question 6

Briefly discuss the role of the large intestine in drug metabolism.

Answer 6

The large intestine contains micro-organisms capable of performing various biotransformations reactions. These reaction can alter the drug’s structure and activity.

Question 7

Briefly discuss the role of the stomach in drug metabolism.

Answer 7

Drugs can be metabolized by gastric acid in the stomach. This can lead to the breakdown of the drug before it is absorbed into the bloodstream.

Question 8

What are some intracellular locations of enzymes involved in biotransformation of drugs?

Answer 8

endoplasmic reticulum, mitochondria, cytosol, lysosomes, nuclear membranes, plasma membrane

Question 9

(a) What is the microsomal mixed function oxidase system (MFO)?
(b) What is another name for the MFO system?

Answer 9

(a) The microsomal mixed function oxidase system is a crucial enzyme system found in the liver and other tissues that plays a significant role in the metabolism of various substances.

(b) It is also called the cytochrome P450 system.

Question 10

What are the primary components of the MFO system?

Answer 10

cytochrome P450 enzymes, NADPH-cytochrome P450 reductase, and cytochrome b5

Question 11

What type of reactions does the MFO system catalyze?

Answer 11

Mixed-function oxidation reactions, where one atom of oxygen is incorporated into the substrate (hydroxylation), and the other is reduced to water.

Question 12

Why is the MFO system medically significant?

Answer 12

Its activity can influence the effectiveness and toxicity of drugs, with variations in cytochrome P450 enzymes among individuals affecting drug metabolism, efficacy, and risk of adverse effects.

Question 13

How can the activity of the MFO system be regulated?

Answer 13

It can be induced or inhibited by various substances, such as certain drugs and environmental chemicals, which can increase the production of cytochrome P450 enzymes.

Question 14

List some inducers of P450 enzymes.

Answer 14

carbamazepine, rifampin, alcohol, phenytoin, griseofulvin, phenobarbital, sulphonylureas

Question 15

List some inhibitors of P450 enzymes.

Answer 15

valproate, ketoconazole, isoniazid, sulfonamides, chloramphenicol, amiodarone, erythromycin, quinidine, grape fruit juice

Question 16

Name the cytochrome P450 dependent reactions.

Answer 16

(1) Oxidative dealkylation
(2) Desulfuration
(3) Deamination
(4) Aromatic hydroxylation
(5) Sulfoxidation
(6) Peroxidation

Further notes:
dehydration is not; it is catalysed by dehydrogenases

Question 17

Briefly discuss factors that influence drug metabolism.

Answer 17

(1) Age: Metabolic activity changes from prenatal development through adulthood, with neonates and elderly individuals typically having reduced metabolism.

(2) Sex: Some studies show that CYP450 activity, particularly CYP3A4, is higher in females than males, while other systems may have higher activity in males.

(3) Nutritional Status: A balanced diet with sufficient proteins, vitamins, and minerals (e.g., copper, zinc, calcium) supports normal enzymatic activity, while deficiencies impair metabolism.

(4) Disease State: Liver diseases like cirrhosis damage hepatocytes and reduce metabolic capacity.

(5) Medications: Some drugs act as inhibitors, inducers, or substrates of CYP450 enzymes, altering the metabolism of concurrently administered medications.

(6) Genetics: Genetic variations affect the expression and activity of CYP450 enzymes, leading to differences in drug metabolism efficiency among individuals.

Question 18

What happens to drug metabolism with advanced age?

Answer 18

(1) decreased metabolization due to decrease in hepatic mass and hepatic blood flow
(2) phase I metabolism decreases affecting drugs like diazepam
(3) therefore drug in phase II are safer (acetaminophen, lorazepam)

Further notes:
“Therefore, drugs that undergo Phase II metabolism, such as acetaminophen and lorazepam, are often considered safer for elderly patients. They are metabolized and excreted more predictably, reducing the risk of accumulation and toxicity.”

Question 19

Outline some of the main substrates of the CYP450 system.

Answer 19

(1) NSAIDs
(2) Beta blockers
(3) Warfarin
(4) Statins
(5) Antiphsycotics
(6) Theophylline
(7) Ethanol

Further notes:
💊 NSAIDs (Nonsteroidal Anti-Inflammatory Drugs): These drugs reduce inflammation, pain, and fever by inhibiting the production of prostaglandins, which are chemicals in the body that promote inflammation, pain and fever.

💊 Beta blockers: These medications lover blood pressure and reduce heart rate by blocking the effects of adrenaline (epinephrine) on beta receptors in the heart and blood vessels.

💊 Warfarin: An anticoagulant that prevents blood clots from forming or growing larger by inhibiting the synthesis of vitamin K-dependent clotting factors.

💊 Statins: These drugs lower cholesterol levels by inhibiting the enzyme HMG-CoA reductase, which is involved in the production of cholesterol in the liver.

💊 Antipsychotics: Medications used to manage psychosis, including delusions, hallucinations, and disordered thinking, primarily in conditions like schizophrenia and bipolar disorder. They work by altering the effects of neurotransmitters in the brain.

💊 Theophylline: A bronchodilator used to treat respiratory diseases such as asthma and chronic obstructive pulmonary disease (COPD). It relaxes the muscles in the airways and decreases the lung’s response to irritants.

Question 20

All of the following are possible consequences of Phase I [non synthetic], biotransformation reactions EXCEPT …
A. production of a pharmacologically inactive metabolite
B. conversion of one pharmacologically active substance to another active substance
C. conversion of a pharmacologically inactive substance to an active substance
D. combination of a drug with an endogenous substance
E. production of a toxic metabolite

Answer 20

D. combination of a drug with an endogenous substance

Question 21

Which of the following is correct?
A. Phase I reactions always inactivate drugs
B. Phase II reactions always inactivate drugs
C. Half life of a drug is half the time necessary for its elimination
D. Protamine sulphate and heparin demonstrate physiological antagonism
F. Rifampicin and cimetidine have opposite effects on liver microsomal enzymes

Answer 21

F. Rifampicin and cimetidine have opposite effects on liver microsomal enzymes

Further notes:
(1) Protamine sulphate is a drug used to reverse the anticoagulant effects of heparin in cases of overdose or during surgery.
(2) Heparin is an anticoagulant that prevents blood clots from forming or growing larger.
(3) Rifampicin is an antibiotic used to treat various bacterial infections, including tuberculosis.
(4) Cimetidine is a histamine H2 receptor antagonist that reduces stomach acid production, used to treat ulcers and gastroesophageal reflux disease (GERD).